The present invention relates to inhibitors of p38, a mammalian protein kinase is involved in cell proliferation, cell death and response to extracellular stimuli. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.
Protein kinases are involved in various cellular responses to extracellular signals. Recently, a family of mitogen-activated protein kinases (MAPK) has been discovered. Members of this family are Ser/Thr kinases that activate their substrates by phosphorylation [B. Stein et al., Ann. Rep. Med. Chem., 31, pp. 289-98 (1996)]. MAPKs are themselves activated by a variety of signals including growth factors, cytokines, UV radiation, and stress-inducing agents.
One particularly interesting MAPK is p38. p38, also known as cytokine suppressive anti-inflammatory drug binding protein (CSBP) and RK, is isolated from murine pre-B cells that are transfected with the lipopolysaccharide (LPS) receptor, CD14, and induced with LPS. p38 has since been isolated and sequenced, as has the cDNA encoding it in humans and mouse. Activation of p38 has been observed in cells stimulated by stress, such as treatment of lipopolysaccharides (LPS), UV, anisomycin, or osmotic shock, and by treatment with cytokines, such as IL-1 and TNF.
Inhibition of p38 kinase leads to a blockade in the production of both IL-1 and TNF. IL-1 and TNF stimulate the production of other proinflammatory cytokines such as IL-6 and IL-8 and have been implicated in acute and chronic inflammatory diseases and in post-menopausal osteoporosis [R. B. Kimble et al., Endocrinol., 136, pp. 3054-61 (1995)].
Based upon this finding it is believed that p38, along with other MAPKs, have a role in mediating cellular response to inflammatory stimuli, such as leukocyte accumulation, macrophage/monocyte activation, tissue resorption, fever, acute phase responses and neutrophilia. In addition, MAPKs, such as p38, have been implicated in cancer, thrombin-induced platelet aggregation, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and neurodegenerative disorders. Inhibitors of p38 have been implicated in the area of pain management through inhibition of prostaglandin endoperoxide synthase-2 induction. Other diseases associated with Il-1, IL-6, IL-8 or TNF overproduction are set forth in WO 96/21654.
Others have already begun trying to develop drugs that specifically inhibit MAPKs. For example, PCT publication WO 95/31451 describes pyrazole compounds that inhibit MAPKs, and, in particular, p38. However, the efficacy of these inhibitors in vivo is still being investigated.
Accordingly, there is still a great need to develop other potent, p38-specific inhibitors that are useful in treating various conditions associated with p38 activation.
The present invention addresses this problem by providing compounds that demonstrate strong and specific inhibition of p38.
These compounds have the general formulae: 
or pharmaceutically acceptable salts thereof, wherein each of Q1 and Q2 are independently selected from 5-6 membered aromatic carbocyclic or heterocyclic ring systems, or 8-10 membered bicyclic ring systems comprising aromatic carbocyclic rings, aromatic heterocyclic rings or a combination of an aromatic carbocyclic ring and an aromatic heterocyclic ring.
The rings that make up Q1 are substituted with 1 to 4 substituents, each of which is independently selected from halo; C1-C3 alkyl optionally substituted with NRxe2x80x22, ORxe2x80x2, CO2Rxe2x80x2 or CONRxe2x80x22; Oxe2x80x94(C1-C3)-alkyl optionally substituted with NRxe2x80x22, ORxe2x80x2, CO2Rxe2x80x2 or CONRxe2x80x22; NRxe2x80x22; OCF3; CF3; NO2; CO2Rxe2x80x2; CONRxe2x80x2; SRxe2x80x2; S(O2)N(Rxe2x80x2)2; SCF3; CN; N(Rxe2x80x2)C(O)R4; N(Rxe2x80x2)C(O)OR4; N(Rxe2x80x2)C(O)C(O)R4; N(Rxe2x80x2)S(O2)R4; N(Rxe2x80x2)R4; N(R4)2; OR4; OC(O)R4; OP(O)3H2; or Nxe2x95x90Cxe2x80x94N(Rxe2x80x2)2.
The rings that make up Q2 are optionally substituted with up to 4 substituents, each of which is independently selected from halo; C1-C3 straight or branched alkyl optionally substituted with NRxe2x80x22, ORxe2x80x2, CO2Rxe2x80x2, S(O2)N(Rxe2x80x2)2, Nxe2x95x90Cxe2x80x94N(Rxe2x80x2)2, R3, or CONRxe2x80x22; Oxe2x80x94(C1-C3)-alkyl; Oxe2x80x94(C1-C3)-alkyl optionally substituted with NRxe2x80x22, ORxe2x80x2, CO2Rxe2x80x2, S(O2)N(Rxe2x80x2)2, Nxe2x95x90Cxe2x80x94N(Rxe2x80x2)2, R3, or CONRxe2x80x22; NRxe2x80x22; OCF3; CF3; NO2; CO2Rxe2x80x2; CONRxe2x80x2; R3; OR3; NR3; SR3; C(O)R3; C(O)N(Rxe2x80x2)R3; C(O)R3; SRxe2x80x2; S(O2)N(Rxe2x80x2)2; SCF3; Nxe2x95x90Cxe2x80x94N(Rxe2x80x2)2; or CN.
Rxe2x80x2 is selected from hydrogen, (C1-C3)-alkyl; (C2-C3)-alkenyl or alkynyl; phenyl or phenyl substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl.
R3 is selected from 5-6 membered aromatic carbocyclic or heterocyclic ring systems.
R4 is (C1-C4)-alkyl optionally substituted with N(Rxe2x80x2)2, ORxe2x80x2, CO2Rxe2x80x2, CON(Rxe2x80x2)2 or SO2N(R2)2; or a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with N(Rxe2x80x2)2, ORxe2x80x2, CO2Rxe2x80x2, CON(Rxe2x80x2)2, or SO2N(R2)2.
X, if present, is selected from xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O2)xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O2)xe2x80x94N(R2)xe2x80x94, xe2x80x94N(R2)xe2x80x94S(O2)xe2x80x94, xe2x80x94N(R2)xe2x80x94C(O)Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94N(R2), xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94N(R2)xe2x80x94, xe2x80x94N(R2)xe2x80x94C(O)xe2x80x94, xe2x80x94N(R2)xe2x80x94, xe2x80x94C(R2)2xe2x80x94, or xe2x80x94C(OR2)2xe2x80x94.
Each R is independently selected from hydrogen, xe2x80x94R2, xe2x80x94N(R2)2, xe2x80x94OR2, SR2, xe2x80x94C(O)xe2x80x94N(R2)2, xe2x80x94S(O2)xe2x80x94N(R2)2, or xe2x80x94C(O)xe2x80x94OR2, wherein two adjacent R are optionally bound to one another and, together with each Y to which they are respectively bound, form a 4-8 membered carbocyclic or heterocyclic ring;
R2 is selected from hydrogen, (C1-C3)-alkyl, or (C1-C3)-alkenyl; each optionally substituted with xe2x80x94N(Rxe2x80x2)2, xe2x80x94ORxe2x80x2, SRxe2x80x2, xe2x80x94C(O)xe2x80x94N(Rxe2x80x2)2, xe2x80x94S(O2)xe2x80x94N(Rxe2x80x2)2, xe2x80x94C(O)xe2x80x94ORxe2x80x2, or R3.
Y is N or C;
Z, if present, is N, NH, or, if chemically feasible, O;
A, if present, is N or CRxe2x80x2;
n is 0 or 1;
R1 is selected from hydrogen, (C1-C3)-alkyl, OH, or Oxe2x80x94(C1-C3)-alkyl.
In another embodiment, the invention provides pharmaceutical compositions comprising the p38 inhibitors of this invention. These compositions may be utilized in methods for treating or preventing a variety of disorders, such as cancer, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, viral diseases and neurodegenerative diseases. These compositions are also useful in methods for preventing cell death and hyperplasia and therefore may be used to treat or prevent reperfusion/ischemia in stroke, heart attacks, and organ hypoxia. The compositions are also useful in methods for preventing thrombin-induced platelet aggregation. Each of these above-described methods is also part of the present invention.